Course and Treatment of Mood and Disorders During Pregnancy : Lessons Learned Across Two Decades

Lee S. Cohen, MD Director, Ammon-Pinizzotto Center for Women’s Mental Health Massachusetts General Hospital Edmund and Carroll Carpenter Professor of Psychiatry Harvard Medical School

www.mghcme.org Disclosures

My spouse/partner and I have the following relevant financial relationship with a commercial to disclose:

12-Month Disclosure

Research Support for the National Pregnancy Registry for Atypical Antipsychotics: Alkermes Biopharmaceuticals; Otsuka Pharmaceuticals; Sunovion Pharmaceuticals, Inc.; Teva Pharmaceuticals; Janssen Pharmaceutica ;

Other research support: Brain & Behavior Research Foundation; JayMac Pharmaceuticals; National Institute on Aging; National Institutes of Health; SAGE Therapeutics

Advisory/Consulting: Alkermes Biopharmaceuticals ,Praxis Precision Medicines, Inc.(through MGH Clinical Trials Network Initiative); Honoraria: None Royalty/patent, other income: None

www.mghcme.org Reproductive Psychiatry and the COVID-19 Pandemic

• Family planning and the pandemic • Telemedicine and implications for pregnancy and postpartum period • Infertility treatment and the pandemic • Perinatal anxiety during the COVID 19 crisis • Importance of euthymia during pregnancy • Reframing postpartum experience

JAMA Psychiatry. Published online July 15, 2020. doi:10.1001/jamapsychiatry.2020.1947 https://womensmentalhealth.org/obgyn/reproductive-psychiatry-during-the-covid-19-pandemic/

www.mghcme.org3 Virtual Rounds at CWMH during COVID : Wednesdays at 2 PM

https://womensmentalhealth.org/posts/resource-join-us-for-virtual-rounds-at-the-center-for-womens-mental-health-on-wednesdays/ www.mghcme.org Treatment considerations for women with MDD in pregnancy and the postpartum period

• during pregnancy is strongest predictor of postpartum depression • Nothing is more important maternal euthymia

www.mghcme.org Major Depression During Pregnancy

Are pregnant women protected against relapse or new onset of major depression?

O’Hara et al. J Abnorm Psychol. 1990 Evans et al. BMJ. 2001 Yonkers et al. Epidemiology 2011 Roca et al. J Affective Disorders 2013

www.mghcme.org6 www.mghcme.org Time to Relapse in Patients Who Maintained or Discontinued Antidepressant

1

0.9

0.8

0.7 Maintained (N = 82) 0.6

0.5

0.4

0.3 Discontinued (N = 65)

0.2

0.1 Percentage of Patients Remaining Well 0 0 12 24 36 Gestational Age Cohen LS, et al. JAMA. 2006

www.mghcme.org8 Womensmentalhealth.org

9 www.mghcme.org Psychotropic Drug Use in Pregnancy

• Medications used when risk to mother and fetus from disorder outweighs risks of pharmacotherapy • Optimum risk/benefit decision for psychiatrically ill pregnant women • Patients with similar illness histories make different decisions regarding treatment during pregnancy • No decision is risk-free • Collaborative, patient-centered approach required

Henshaw Fam Plann Perspect. 1998

www.mghcme.org10 Treatment of Depression During Pregnancy: Lessons Learned and New Directions

• Focus of concern regarding known and unknown risks of fetal exposure to psychiatric medications is increasingly balanced by data supporting risk of exposure to disorder, stress and HPA-axis dysregulation on fetoplacental unit

• Enhanced appreciation for impact of disorder and on long term behavioral outcomes

www.mghcme.org11 Maternal Stress or Depression IN UTERO

Programming of Fetal HPA Axis Dysregulation of the HPA Axis Dysregulation of HPA Axis

Increased Elevated Elevated CRH Reactivity Cortisol Levels to Stress

Increased Vulnerability to Mood and Anxiety Disorders

www.mghcme.org www.mghcme.org 14

What is the Safest Antidepressant for Women of Childbearing Age?

www.mghcme.org14 Phasing Out: FDA Pregnancy Categories

• Category A: – Well controlled studies in human pregnancy show no increased risk to the fetus • Category B: – Animal studies show no increased risk to the fetus OR – Animal studies show an increased risk to the fetus but well controlled human studies do not. • Category C: – Animal studies show an increased risk to the fetus and there are no well controlled studies in human pregnancy OR – There aren’t any animal studies or well controlled human studies.

www.mghcme.org http://womensmentalhealth.org/posts/fda-finalizes-guidelines-pregnancy-lactation-labeling-information/ www.mghcme.org Timeline to Changes in Product Labeling

Required Submission Date of NDAs, BLA, ESs PLLR Format New Applications Submitted on or after 6/30/2015 At time of submission ------PLLR Implementation Date (6/30/2015) ------Approved 6/30/2001 to 6/29/2002 6/30/2018 Approved 6/30/2005 to 6/29/2007 Approved 6/30/2007 to 6/29/2015 6/30/2019 Or pending on 6/30/2015 Older Approved Applications Approved 6/30/2002 to 6/29/2005 6/30/2020 Not required to be in PLLR For applications approved prior to format. However, must 6/30/2001 in old format labeling remove Pregnancy Category by 6/29/2018

Do not distribute www.mghcme.org SSRI Use During Pregnancy

• Recent findings and more data inform the pharmacologic treatment of depression during pregnancy – Consistent conclusions that the absolute risk of SSRI exposure in pregnancy is small1-3 – Consistent pattern of malformations with SSRI exposure is lacking – Case-control studies reveal inconsistent data regarding teratogenic risk of individual SSRIs4-9 Reproductive safety data on SSRIs exceed what is known about most other medicines used in pregnancy

1 Louik C et al. N Engl J Med 2007; 2 Einarson TR, Einarson A. Pharmacoepidemiol Drug Saf 2005; 3 Einarson A, et al. Am J Psychiatry 2008; 4 Alwan S, et al. N Engl J Med 2007; 5 Greene MF. N Engl J Med 2007; 6 Hallberg P, Sjoblom V. J Clin Psychopharmacol 2005; 7Wogelius P, et al. Epidemiology 2006; 8 www.gsk.ca/english/docs-pdf/PAXIL_PregnancyDHCPL_E-V4.pdf Dear Healthcare Professional (3/17/08); 9 www.fda.gov/medwatch/safety/2005/Paxil_dearhcp_letter.pdf Dear Healthcare Professional (3/17/08); Grigoriadis et al. J Clin Psychiatry 2013.

www.mghcme.org18 Read our blog post on this topic: https://womensmentalhealth.org/posts/antidepressant-birth-defects/

Anderson KN, Lind JN, Simeone RM, Bobo WV, Mitchell AA, Riehle-Colarusso T, Polen KN, Reefhuis J. Maternal Use of Specific Antidepressant Medications During Early Pregnancy and the Risk of Selected Birth Defects. JAMA Psychiatry. 2020 Aug 5:e202453. Huybrechts KF, Palmsten K, Avorn J, Cohen LS, Holmes LB, Franklin JM, Mogun H, Levin R, Kowal M, Setoguchi S, Hernández-Díaz S. Antidepressant use in pregnancy and the risk of cardiac defects. N Engl J Med. 2014 Jun 19;370(25):2397-407. Wisner KL, Oberlander TF, Huybrechts KF. The Association Between Antidepressant Exposure and Birth Defects-Are We There Yet? JAMA Psychiatry. 2020 Aug 5. www.mghcme.org • No evidence of increased risk for major malformations or cardiovascular malformations in children of pregnant women exposed to SSRIs

www.mghcme.org Cardiovascular Malformation and Fetal SSRI Exposure

Huybrechts et al. NEJM 2014. www.mghcme.org “Poor Neonatal Adaptation” and SSRI Use During Pregnancy 22

• Consistent data: Late trimester exposure to SSRIs is associated with transient , agitation, jitteriness, and tachypnea (25-30%) • Overall studies do not adequately control for maternal mental health condition, adequate blinding of exposure in neonatal assessments • Clinical implication: Should women be treated with antidepressants late in pregnancy and during labor and delivery (Warburton et al. 2010) • Are any subgroups of newborns vulnerable to enduring symptoms beyond the first days of life ?

Levinson-Castiel R, et al. Arch Pediatr Adolesc Med. 2006 Chambers CD, et al. N Engl J Med. 2006 Chambers, BMJ, 2009 CWMH Blog, July 27 2005: http://womensmentalhealth.org/posts/neonatal-symptoms-after-in-utero-exposure-to-ssris/

www.mghcme.org22 What are the Long-term Neurobehavioral Effects of Prenatal Exposure to an Antidepressant?

www.mghcme.org23 Full blog post: https://womensmentalhealth.org/posts/antidepressants-neurodevelopment/

Singal D, Chateau D, Struck S, Lee JB, Dahl M, Derksen S, Katz LY, Ruth C, Hanlon-Dearman A, Brownell M. In Utero Antidepressants and Neurodevelopmental Outcomes in Kindergarteners. Pediatrics. 2020 May;145(5). Andrade C. Genes as Unmeasured and Unknown Confounds in Studies of Neurodevelopmental Outcomes After Antidepressant Prescription During Pregnancy. J Clin Psychiatry. 2020 May 26;81(3):20f13463. Free Article Rommel AS, Bergink V, Liu X, Munk-Olsen T, Molenaar NM. Long-Term Effects of Intrauterine Exposure to Antidepressants on Physical, Neurodevelopmental, and Psychiatric Outcomes: A Systematic Review. J Clin Psychiatry. 2020 May 12;81(3):19r12965. Andrade C. Offspring Outcomes in Studies of Antidepressant-Treated Pregnancies Depend on the Choice of Control Group. J Clin Psychiatry. 2017 Mar;78(3):e294-e297. Free Article www.mghcme.org www.mghcme.org www.mghcme.org26 Treatment Guidelines Depression : Does Severity Drive Treatment Recommendations (and Patient Choice)

• Psychotherapy: First-line for mild to moderate MDD • Lifestyle components: Nutrition, weight management, prenatal care ; treatment for co-morbid substance abuse • Evidence base for CBT , Behavioral Activation and MBCT (prevention) • Women trying to conceive who have histories of MDD: –Encourage period of euthymia –Sustained remission: consider tapering and discontinuing ? –More recently depressed or with symptoms: consider remaining on medication, optimizing medication • Pregnant women with severe MDD: Medication is first-line • Pregnant women on antidepressants during pregnancy: take into account patient preferences, previous course of illness • Medication selection should be based on known safety information MDD, major depressive disorder. Yonkers KA et al. Obstet Gynecol. 2009;114(3):703-713.

www.mghcme.org Treatment of Depression During Pregnancy: Lessons Learned

• Treatment decisions are complex (maternal and fetal benefits and risks) • Absolute quantification of risk associated with fetal exposure to medication or maternal disease is impossible • No treatment decision is “perfect” - Each treatment decision should try to optimize pregnancy outcomes for the mother and her child - Consider the risks of untreated disease and the risks of medication treatment -wisdom of changing AD dose proximate to delivery is sparse

Kallen Obstet Gynecol Int. 2012 Palmsten and Hernandez-Diaz Epidemiology 2012

www.mghcme.org Summary of treatment considerations for women with MDD in pregnancy (cont.)

• Depression during pregnancy is strongest predictor of postpartum depression • There are known and unknown risks associated with AD use during pregnancy • Adverse effects of depression in pregnancy on patient, infant and families • Nothing trumps maternal euthymia

www.mghcme.org 30

Bipolar Disorder During Pregnancy

www.mghcme.org30 Relapse of During Pregnancy

Viguera et al. Am J Psychiatry 2007 www.mghcme.org31 Pharmacologic Treatment of Pregnant Women with Bipolar Disorder: Weighing Imperfect Options

• Commonly employed antimanic agents are either known teratogens or have sparse available reproductive safety data • Risks of untreated psychiatric illness • Risk of discontinuing maintenance psychotropic medications

Cohen LS, et al. JAMA. 1994 Steer RA, et al. J Clin Epidemiol. 1992 Orr ST, et al. Am J Prev Med. 1996 Suppes T, et al. Arch Gen Psychiatry. 1991 Faedda GL, et al. Arch Gen Psychiatry. 1993 Baldessarini RJ, et al. Clin Psychiatry. 1996 www.mghcme.org32 33 National Pregnancy Registry for Atypical Antipsychotics

A NEW Research Study at the Massachusetts General Hospital Center for Women’s Mental Health

To determine the safety of atypical antipsychotics in pregnancy for women and their babies

Participation will involve 3 brief phone interviews over approximately 8 months

Call Toll-Free: 1-866-961-2388

www.mghcme.org33 March 2016

• Primary aim: determine the risk of major malformations among infants exposed to second-generation antipsychotics • Prospectively enrolled 487 women • The odds ratio for major malformations comparing exposed and unexposed infants was 1.25 (95% CI=0.13-12.19) • Current data indicate that second-generation antipsychotics are not major teratogens • Study is ongoing and continues to enroll women

www.mghcme.org National Pregnancy Registry for Atypical Antipsychotics: Interim Findings Aggregate Sample : May 2020

• Prospective study – current sample > 2000 • As of May, 2020: – 1906 subjects enrolled – 640 with 1st trimester exposures enrolled w/ evaluable data at time of analysis – 704 in comparison group ( non-exposed) – Exposure group: 16 malformations (2.5% prevalence) – Control group: 14 malformations (2.0% prevalence) – Odds ratio major malformations ( exposed versus controls) 1.48 (95% CI, 0.625 - 3.517) • Preliminary conclusions: atypical antipsychotics are not major teratogens but more data are needed to narrow the interval www.mghcme.org National Pregnancy Registry for Atypical Antipsychotics: Interim Findings - Aripiprazole

• Prospective study • As of May 2020: – 1906 enrolled – 163 1st trimester exposures enrolled w/ evaluable data at time of analysis, 7 cases malformations versus 14 of the 690 unexposed – Prevalence malformations = 4.29 % (exposed) vs. 1.99 % – Adjusted odds ratio; 1.35 (95% confidence interval [CI]= (0.433,4.197). • Preliminary conclusions: aripiprazole is not likely a major teratogen ;more data are needed to narrow the confidence interval www.mghcme.org Presented at ASCP, Cohen et al., 2020 Reproductive Safety of Quetiapine : NPRAA FIndings

Cohen et al., 2018; Amer J Psychiatry www.mghcme.org https://womensmentalhealth.org/posts/12021/?doing_wp_cron=1506358912.7760159969329833984375

www.mghcme.org and Pregnancy

• Lithium Register of Babies 1970s • Ebstein’s Anomaly: 0.05 – 0.1% risk • Recent analysis from Medicaid database shows dose-dependent increase in risk of cardiovascular anomalies

39 www.mghcme.org Valproic Acid and Pregnancy

• Overall risk of malformations elevated (6-10%): neural tube defects, cardiac anomalies, cleft lip/palate, limb abnormalities • Dose dependent: Risk for major malformations highest (25.2%) in women on high dose valproate (above 1450 mg/day) • Higher rates associated with polytherapy • Neurodevelopmental sequelae: Increased risk of tautism spectrum disorders, behavioral problems, lower IQ • Folic acid appears to ameliorate risk of autism spectrum disorders but not risk of malformations • UK and France have banned use of valproic acid in certain population s of reproductive age women

40 www.mghcme.org Other Antiepileptic Drugs and Pregnancy

Recent study from EUROCAT •107 of 1957 for carbamazepine = 5·5% •6 of 152 for topiramate = 3·9%, oral clefts •10 of 333 for oxcarbazepine = 3·0% •74 of 2514 for lamotrigine = 2·9%

Inadequate data on the use of gabapentin, less than 350 exposures

41 www.mghcme.org Cognitive Function in 6 year olds Following Fetal Exposure to AED’s

Child IQ at 6 years, by exposure to maternal antiepileptic drug use and periconceptional folate

Mean (95% CIs) are shown for folate (solid lines) and no folate (dashed lines).

Meador, et al. Lancet Neurol. 2013 www.mghcme.org Treatment of Bipolar Illness During Pregnancy: What is a Reasonable Strategy?

• Lithium and lamotrigine have well characterized reproductive safety profiles, low absolute risks • Lithium may be the best characterized and reasonable alternative for women who require an anti-manic agent but its use is declining • Lamotrigine appears reasonable for the prevention of depressive episodes ( but not for per se) • Atypical antipsychotics have growing body of data and do not at this time appear to be major teratogens • More human pregnancy data available for older medications in the class • May be reasonable to continue during pregnancy, particularly if patient has had good response, psychotic symptoms, is a lithium non-responder, or atypical was critical in affording euthymia

Cohen LS, J Clin Psychiatry 2007 (suppl 9). www.mghcme.org43 Benzodiazepines

• Methodological issues have confounded reports: dose, duration, class of BZD, other drug exposures, recall bias • Risk of oral clefts following first trimester exposure (0-0.6%) • Review of 12 studies (2001-2011): Most studies show no increase in malformations, no consistent pattern of defects

Altshuler, Cohen et al. Am J Psychiatry. 1996. Dolovich, et al. BMJ. 1998.

www.mghcme.org Stimulants during Pregnancy

• From the current available data from prospective, retrospective and case control studies it can be concluded that none of the medications (except guanfacine, where data is unavailable) used for the treatment of ADHD is a major human teratogen.

• Available data do suggest the possibility that psychostimulants, especially amphetamines, may increase the risk of preeclampsia and possibly certain other adverse gestational outcomes; the absolute risk, however, is low.

• Long-term neurodevelopmental studies on the offspring are sparse

• If treatment is pursued, methylphenidate, amphetamine and bupropion appear to be better choices than other medication where reproductive safety data are sparse

www.mghcme.org Cannibus and Pregnancy

www.mghcme.org ECT During Pregnancy

• Treatment of choice when expeditious management is imperative • Use in delusional depression, mania • External fetal monitoring, ultrasonography • Comprehensive treatment team

www.mghcme.org MGH Perinatal Depression Scale

www.mghcme.org